Ribociclib (1), or 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, in the form of a succinate salt, is the active ingredient in KISQALI®, which is indicated, in combination with an aromatase inhibitor, as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced or metastatic breast cancer.

WO 2012/064805 A1 discloses a ‘non-hydrate’ form and a hydrate form of Ribociclib succinate. However, the non-hydrate form is hygroscopic and converts to the hydrate form upon exposure to high humidity levels, whereas the hydrate form is reported to have 60 times lower solubility compared to the non-hydrate form. Furthermore, the method of preparation of the hydrate form in WO 2012/064805 A1, by exposure of the non-hydrate form to high humidity, is impractical to execute on commercial scale.
According to the European CHMP Assessment Report for KISQALI® (EMEA/H/C/004213/0000), the drug substance Ribociclib succinate, which by reference to the chemical formula in the report is in the anhydrous form, has both low solubility and moderate permeability, placing it in Class IV of the Biopharmaceutics Classification System (BCS). Of the four BCS Classes, owing to their low solubility and poor permeability, Class IV drug substances present the most challenges to achieving adequate bioavailability.
Furthermore, according to the CHMP report for KISQALI®, the drug substance Ribociclib succinate in the approved tablet exhibits hygroscopicity. Consistent with this hygroscopicity, the CHMP report describes packaging measures typically used for the exclusion of moisture, such as use of ‘very tight’ quadruple lamination for the storage of the Ribociclib succinate drug substance, and blister packaging for the drug product. Additionally, the coating of KISQALI® tablets comprises polyvinyl alcohol, which, according to WO 2016/166703 A1, is useful as a moisture barrier for Ribociclib succinate tablets.
The solubility of individual crystalline forms of a drug substance in an aqueous environment often correlates to their relative bioavailability since the manner in which the crystalline form dissolves can correspond to the amount of the drug substance that is available to be absorbed into the body, and thereby provide the intended therapeutic effect. One measure of solubility is intrinsic dissolution rate (IDR), which is the dissolution rate of a substance under constant surface area conditions. For low solubility substances such as Ribociclib succinate that are classified as BCS Class IV, higher IDR values can correlate with higher bioavailability following administration. Prediction of the solubility and IDR of an as yet undiscovered crystalline form of a substance is currently not possible.
Different crystalline forms of the same compound may have different crystal packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different crystalline forms may have different stability properties such that a particular crystalline form may be less sensitive to heat, relative humidity (RH) and/or light. Different crystalline forms of a compound may also be more susceptible to moisture uptake, resulting in a potential alteration of physical characteristics of the form such as flowability, density or compressibility, which can lead to problems during formulation/tabletting and/or to changes in dissolution rate of the formulated drug product. For example, unintended absorption of moisture by a hygroscopic crystalline form of a drug substance can alter its compressibility during tabletting, resulting in a softer tablet having a faster dissolution rate following administration. A particular crystalline form may provide more favourable compressibility and/or density properties, thereby providing more desirable characteristics for formulation and/or product manufacturing. Differences in stability between solid forms of a drug may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for more suitable product qualities, including a dosage form that is more resistant to discolouration when comprised of a specific crystalline form. Particular crystalline forms may also have different solubilities, thereby providing different pharmacokinetic parameters, which allow for specific crystalline forms to be used in order to achieve specific pharmacokinetic targets. Differences in solubility between crystalline forms are particularly relevant for compounds exhibiting low aqueous solubility, such as BCS Class IV drug substances, where even a modest increase in solubility can provide a beneficial enhancement in bioavailability.
Although general approaches to crystalline form screening of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible. For example, in the case of Ribociclib succinate, which is reported to exist in anhydrous and hydrated crystalline forms, an anhydrous crystalline form can arise even when using an aqueous solvent system. As reported in US 2017/0342075 A1, anhydrous Form I Ribociclib succinate can be prepared from stirring the non-hydrate form of the salt that is described in WO 2012/064805 A1 in a mixture of water and acetonitrile at 50° C. for 48 hours. Accordingly, it is not possible to extend generalities to the number and kinds of crystalline forms that can exist for Ribociclib succinate, or to what methods will be suitable for the preparation of any given crystalline form. Furthermore, prediction of the properties of any unknown crystalline forms, and how they will differ from other crystalline forms of the same compound, remains elusive (Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002, page 9).
Due to the classification of Ribociclib succinate as a BCS Class IV drug substance, and the hygroscopicity and/or instability of Ribociclib succinate anhydrous crystalline forms, there exists a need for novel crystalline forms of Ribociclib succinate having improved properties for use in providing drug products containing Ribociclib succinate, and commercially amenable processes for their manufacture.